Acute kidney injury (AKI) is a common problem in both tertiary care centers as well as in the developing world. AKI often arises from injuries such as trauma, severe infection, sepsis, medications and contrast agents, or following major surgery. AKI is common among patients requiring intensive care on hospital admission, often requiring the use of dialysis. Renal failure is often associated with damage to remote (nonrenal) organs, particularly the lungs, with increased pulmonary vascular permeability and pulmonary hemorrhage (Kramer et al., 1999, Kidney Int. 55:2362-7).
Acute kidney injury involves cell necrosis as well as NETosis, a programmed neutrophil death leading to expulsion of nuclear chromatin leading to neutrophil extracellular traps (NETs). ETosis is a programmed form of cell death of mostly neutrophils (referred to as NETosis) and other granulocytes (Brinkmann et al., 2004, Science 303:1532). NETosis causes an explosion-like directed expulsion of chromatin generating a meshwork called neutrophil extracellular traps (NETs), which immobilize and kill bacteria during infections (Brinkmann et al., 2004, Science 303:1532). Cytokine-induced NETosis also drives sterile injury including necrotizing GN (Kessenbrock et al., 2009, Nat Med 15:623; Kambas et al., 2013, Ann Rheum Dis 73:1854; Nakazawa et al., 2012, Front Immunol 3:333; Tsuboi et al., 2002, J Immunol 169:2026). Many cytosolic or chromatin-related components could account for the toxic and pro-inflammatory effect of NETs, such as proteolytic enzymes or intracellular molecules with immunostimulatory effects, referred to as danger-associated molecular patterns (DAMPs) (Rock et al., 2010, Annual Review of Immunology 28:321).
Histones are nuclear proteins that wind up the double-stranded DNA to form chromatin. Dynamic modifications of histone residues regulate gene transcription by determining the accessibility of transcription factors to their DNA binding sites (Helin & Dhanak, 2013, Nature 502:480). When cell necrosis releases histones into the extracellular space they display significant cytotoxic effects (Hirsch, 1958, J Exp Med 108:925; Xu et al., 2009, Nat Med 15:1318; Chaput & Zychlinsky, 2009, Nat Med 15:1245; Allam et al., 2014, J Mol Med 92:465). Histones contribute to fatal outcomes in murine endotoxinemia caused by microvascular injury and activation of coagulation (Xu et al., 2009, Nat Med 15:1318; Abrams et al., 2013, Am J Respir Crit Care Med 187:160; Saffarzadeh et al., 2012, PLoS One 7:e32366; Semeraro et al., 2011, Blood 118:1952). Dying renal cells release extracellular histones that promote septic and post-ischemic acute kidney injury (Allam et al., 2012, J Am Soc Nephrol 23:1375). Further, histones act as DAMPs by activating Toll-like receptor (TLR)-2 and -4 as well as NLRP3 (Allam et al., 2012, J Am Soc Nephrol 23:1375; Allam et al., 2013, Eur J Immunol 43:3336; Semeraro et al., 2011, Blood 118:1952; Huang et al., 2013, J Immunol 191:2665; Xu et al., 2011, J Immunol 187:2626). TLR2/-4-mediated pathology is an essential mechanism of crescentic GN (Brown et al., 2006, J Immunol 177:1925; Brown et al., 2007, J Am Soc Nephrol 18:1732).
A need exists for improved methods and compositions for treatment of remote organ injury induced by acute kidney injury, preferably using histone-neutralizing agents such as anti-histone antibodies or fragments thereof, or agents that inhibit post-translational modification of histones, such as PAD (peptidyl arginine deiminase) inhibitors (Bicker & Thompson, 2013, Biopolymers 99:155-63).